Abstract The induction of plasma cells that secrete antibodies against donor tissue alloantigens is a major barrier to successful transplantation. Moreover, because many plasma cells are exceptionally long-lived, the resulting antibody titers are exceptionally durable. Hence strategies are needed to eliminate long-lived plasma cells that generate allospecific antibodies. A current dominant strategy for depleting plasma cells centers on compounds that interfere with the proteasome. Plasma cells are thought to uniquely require proteasome function to survive. However, for reasons unclear, substantial numbers of allospecific plasma cells resist the action of available proteasome inhibitors (PIs). This issue is compounded by the possibility that newly formed plasma cells, induced by persisting antigens, also contribute substantial amounts of deleterious antibodies. The chief objective of this project is to establish the impact of PIs on newly formed versus long-lived plasma cells, and define how biochemical responses to hypoxia affect mitochondrial apoptosis regulate responses of plasma cells to proteasome blockade. This work will leverage our unique capacity to resolve and characterize newly formed versus long-lived plasma cells. Specifically, we will: 1) Contrast the impact of PIs on newly formed versus long-lived PCs. 2) Test whether hypoxic niches and HIF1-alpha enhance PC resistance to PIs, and 3) Identify PI-induced mitochondrial death and resistance mechanisms in long-lived PCs. These studies will provide unique and needed insights into the mechanisms whereby proteasome inhibition affects allospecific plasma cell survival and function.